RGM (repulsive guidance molecule), which is a GPI-anchored membrane protein with a molecular weight of about 33 kDa, has been initially identified as an axon guidance molecule in the visual system (see Non-Patent Document 1). The RGM family includes three members called RGMa, RGMb and RGMc. Among them, RGMa is re-expressed after central nervous system injury in adult humans and rats as well as at developmental stage, and RGMa inhibition in rat accelerates neurite outgrowth after spinal cord injury and promotes functional recovery (see Non-Patent Document 2). Thus. RGMa is thought to be a neurite inhibitor after central nervous system injury.
RGMa also has been reported to have effects in the immune system. RGMa is expressed on dendritic cells and acts on T cells, thereby enhancing adhesion of T cells to ICAM-1 and fibronectin and inducing cytokine production (Patent Document 4). In a mouse model of multiple sclerosis, administration of anti-RGMa antibody suppresses symptoms due to encephalomyelitis and also shows effects of suppressing onset and relapse. It is thought, that anti-RGMa antibody binds to RGMa expressed on dendritic cells to inhibit the activation of T cells, thereby exerting effects on multiple sclerosis.
The signal transduction mechanism of RGMa is also being elucidated, and neogenin protein has been reported as an RGMa receptor (Patent Document 3). Neogenin is a single-transmembrane protein expressed on neurons and T cells.
RGMa binds to neogenin on a cell membrane to induce intracellular RhoA activation and Ras inactivation, thereby providing a neurite outgrowth inhibitory effect. Meanwhile, neogenin is known to cause apoptosis in the absence of RGMa binding in a developing chicken brain (Matsunaga et al., Dev. Growth Differ. 46, 481, 2004). Thus, the RGMa/neogenin pathway is thought to have two conflicting effects of promoting neuronal survival, which is a favorable effect for nerve regeneration, and of inhibiting neurite outgrowth, a negative effect.
As a pharmaceutical agent targeting RGM, Patent Document 1 discloses an axon regeneration promoting agent containing an anti-RGM neutralizing antibody as an active ingredient. Patent Documents 2 and 3 disclose a therapeutic agent for mechanical damage to brain and spinal cord, an anti-RGM antibody that regulates the binding of RGM to its receptor neogenin. Patent Document 4 discloses medical uses of anti-RGM antibody such as for multiple sclerosis Patent Document 5 discloses therapeutic uses of anti-RGM antibody for diseases including multiple sclerosis, mammalian brain injury, spinal cord injury, apoplexy, neurodegenerative disease and schizophrenia. Furthermore, Patent Document 6 discloses therapeutic uses of RGM modulators such as anti-RGM antibody for spinal cord injury and multiple sclerosis, and Non-Patent Document 3 discloses a therapeutic use for progressive multiple sclerosis.